Role of a new mammalian gene family in the biosynthesis of very long chain fatty acids and sphingolipids.

Whereas the physiological significance of microsomal fatty acid elongation is generally appreciated, its molecular nature is poorly understood. Here, we describe tissue-specific regulation of a novel mouse gene family encoding components implicated in the synthesis of very long chain fatty acids. The Ssc1 gene appears to be ubiquitously expressed, whereas Ssc2 and Cig30 show a restricted expression pattern. Their translation products are all integral membrane proteins with five putative transmembrane domains. By complementing the homologous yeast mutants, we found that Ssc1 could rescue normal sphingolipid synthesis in the sur4/elo3 mutant lacking the ability to synthesize cerotic acid (C(26:0)). Similarly, Cig30 reverted the phenotype of the fen1/elo2 mutant that has reduced levels of fatty acids in the C(20)-C(24) range. Further, we show that Ssc1 mRNA levels were markedly decreased in the brains of myelin-deficient mouse mutants known to have very low fatty acid chain elongation activity. Conversely, the dramatic induction of Cig30 expression during brown fat recruitment coincided with elevated elongation activity. Our results strongly implicate this new mammalian gene family in tissue-specific synthesis of very long chain fatty acids and sphingolipids.

Effects of flavoring and casing ingredients on the toxicity of mainstream cigarette smoke in rats.

A series of in vitro and in vivo studies evaluated the potential effects of tobacco flavoring and casing ingredients. Study 1 utilized as a reference control cigarette a typical commercial tobacco blend without flavoring ingredients, and a test cigarette containing a mixture of 165 low-use flavoring ingredients. Study 2 utilized the same reference control cigarette as used in study 1 and a test cigarette containing eight high-use ingredients. The in vitro Ames Salmonella typhimurium assay did not show any increase in mutagenicity of smoke condensate from test cigarettes designed for studies 1 and 2 as compared to the reference. Sprague-Dawley rats were exposed by nose-only inhalation for 1 h/day, 5 days/wk for 13 wk to smoke from the test or reference cigarettes already described, or to air only, and necropsied after 13 wk of exposure or following 13 wk of recovery from smoke exposure. Exposure to smoke from reference or test cigarettes in both studies induced increases in blood carboxyhemoglobin ((COHb)) and plasma nicotine, decreases in minute volume, differences in body or organ weights compared to air controls, and a concentration-related hyperplasia, squamous metaplasia, and inflammation in the respiratory tract. All these effects were greatly decreased or absent following the recovery period. Comparison of rats exposed to similar concentrations of test and reference cigarette smoke indicated no difference at any concentration. In summary, the results did not indicate any consistent differences in toxicologic effects between smoke from cigarettes containing the flavoring or casing ingredients and reference cigarettes.

Toxicity of formaldehyde vapor in B6C3F1 mice exposed for 13 weeks.

Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 2, 4, 10, 20, or 40 ppm of formaldehyde vapor 6 h/day, 5 days/week for 13 weeks. Clinical abnormalities (dyspnea, listlessness, and hunched posture), significant mortality, and body weight loss were observed in the 40 ppm groups. Pathologic changes were observed in the nose, larynx, trachea, and bronchi of treated males and females and in the uterus and ovaries of treated females. Squamous metaplasia and inflammation were present in the nasal tissues of male and female mice in the 10, 20, and 40 ppm groups and in the larynx of males and females in the 20 and 40 ppm groups. The trachea had squamous metaplasia and hyperplasia of the epithelium in addition to submucosal fibrosis and inflammation in the 20 and 40 ppm groups. In some mice, epithelial-lined, irregular connective tissue bands spanned the tracheal lumen. Metaplasia of the bronchial epithelium was confined to the 40 ppm exposure groups. These effects on the respiratory system were more prevalent in male than in female mice. Hypoplasia of the uterus and ovaries, probably secondary to body weight loss, was confined to the 40 ppm exposure group. In conclusion, 13-week inhalation exposures of B6C3F1 mice to 10, 20, and 40 ppm of formaldehyde vapor induced histologic lesions in the upper respiratory system and concentrations of 40 ppm were lethal to those mice.

Evaluation of the potential for developmental toxicity in rats and mice following inhalation exposure to tetrahydrofuran.

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0, 600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widely used as an industrial solvent) vapors, 6 hr/day, 7 days/week (6-19 days of gestation (DG) for rats; 6-17 DG for mice). Body weights of pregnant rats in the 5000 ppm group were reduced at euthanization. There were no effects on the percentage of live rat fetuses/litter or on the fetal sex ratio. Fetal body weight was significantly reduced for the 5000 ppm group, but the incidence of abnormalities was not increased. Mice in the 1800 and 5000 ppm groups were sedated during exposure; approximately 27% of the mice in the 5000 ppm group died. Mean body and uterine weights of mice were reduced for the 1800 and 5000 ppm groups at euthanization (18 DG), but adjusted maternal weight gain was not affected at 1800 ppm. There was a reduction in the percentage of live fetuses/litter for the mice in 1800 and 5000 ppm groups (95% resorptions in the 5000 ppm group). Fetal weight and sex ratio in mice were not affected. An increase in the incidence of reduced sternebral ossifications was correlated to THF concentration, although differences between groups were not statistically significant. There were no increases in the incidences of other malformations or variations. These results suggest that THF may be embryotoxic in mice, but if the conceptus survives, development as assessed by this experimental design continues in a normal fashion. The no-observable-adverse-effect level (NOAEL) for maternal toxicity was 1800 ppm in both rats and mice. The NOAEL for developmental toxicity was 1800 ppm in rats and 600 ppm in mice.

Chemical and physical characteristics of cellulose insulation particulates, and evaluation of potential acute pulmonary toxicity.

BACKGROUND: During installation of cellulose insulation (CI) in new and older houses, significant quantities of airborne material are generated. This study characterized the chemical and physical properties, and potential acute pulmonary toxicity of CI. METHODS: CI from four manufacturers was analyzed for inorganic additives and trace element impurities. Aerosols were generated and size fractionated. The number and size of fibrous and nonfibrous particles in the respirable fractions were determined. Respirable CI particulates were intratracheally instilled in rats (5 mg/kg) to evaluate potential pulmonary toxicity. RESULTS: CI samples were similar in composition with small differences due primarily to fire retardants. Less than 0.1% of CI was respirable and contained few fibers. Acute exposure to CI caused transient inflammation in the lungs and increased 4-hydroxyproline. Microscopic evaluation revealed a minimal to mild, non-progressing granulomatous pneumonitis. CONCLUSIONS: Low concentrations of respirable particles were found in CI aerosols. Particles consisted primarily of fire retardants with few fibers, and caused mild pulmonary toxicity in rats.